The attributes of Ketamine are well documented throughout the prior art. U.S. Pat. No. 5,817,699 discloses the benefits of Ketamine in an ointment form relating to the treatment of Sympathetic Mediated pain, Neuropathic pain, Myofascial pain, and Parkinson's disease. The advantages of a topical application of Ketamine are clearly set forth in U.S. Pat. No. 5,817,699. The present invention discloses an ointment combining Ketamine with n-butyl-p-aminobenzoate (BAB). The resultant novel ointment is an improvement over the Ketamine ointment, as disclosed in U.S. Pat. No. 5,817,699, for the treatment of Sympathetic Mediated pain, Neuropathic pain, Myofascial & TMJ pain, and further aids in the treatment of Osteoarthritis & SIJ pain.
Ketamine hydrochloride (2-[o-chlorophenyl]-2-[methylamino] cyclohexone hydrochloride) is an anesthetic, but not in the sense of local anesthetics. Local anesthetics block nerve conduction when applied locally to nerve tissue in appropriate concentrations. A local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. Ketamine is a dissociative anesthetic. Dissociative anesthesia is a condition or state of feeling dissociation from the environment by the subject to whom such an agent is administered. Ketamine has traditionally been used as a general anesthetic during induction techniques for surgical or diagnostic procedures. Ketamine's mechanism of action has been compared to that of barbiturates.
Recently there has been growing interest in the role of NMDA (N-methyl-d-aspartate) receptors and their association with Neuropathic pain. NMDA receptors can be found in the hippocampus and cerebral cortex of the brain in addition to the spinal cord. Ketamine has been found to be a potent NMDA receptor antagonist. NMDA receptor antagonists have been found to be very effective in the management of Neuropathic pain.
The administration of Ketamine has usually been via intravenous, oral, subcutaneous or intramuscular routes in order to access venous sites of the NMDA receptors. Ketamine has historically been associated with significant side effects when administered through the aforementioned common routes manifesting as sedative and cognitive impairment. U.S. Pat. Nos. 5,232,950, 5,352,683, 5,543,434 and 5,817,699 disclose the limitations of Ketamine in its common form and applications.
As disclosed in U.S. Pat. No. 5,817,699 studies by the inventors have shown topical Ketamine to be highly effective in the treatment of Neuropathic pain without adversity at doses normally associated with side effects. The pain alleviating benefit of Ketamine has been observed to occur after the onset of side effects (approximately 60 minutes) and dissipate prior to the resolution of side effects (approximately 2 hours). Further studies have shown topical Ketamine to alleviate pain within minutes of application, without proceeding side effects, and to endure for hours to days after a single application.
Studies of an aqueous suspension of n-butyl-p-aminobenzoate, a highly lipid-soluble congener of benzocaine, have been done extensively. The early studies have shown BAB to be quite effective in providing long duration of analgesia via an epidural route in the treatment of intractable cancer pain. The initial impression was that BAB was acting as a neurolytic agent when applied directly to nervous tissue, but subsequent dog studies have shown that not to be the case. Subsequent studies have shown BAB to have long-lasting sensory blockade accompanied by a marked reduction or even absence of pain. It was noted that with the profound sensory blockade, motor, bowel, and bladder function were well preserved. Follow-up studies evaluating BAB's mechanism of action show it to be highly selective for fast sodium channels with little effect on slow sodium channels. This allows BAB to select out C and A-delta nerve fibers, which are responsible for deep achy post injury pain, thus preserving the initial protective nociceptive pain response and motor function of the affected site.
Our clinical studies have demonstrated that when Ketamine and BAB are combined in an ointment for topical use, application to the majority of pain sites has faster and greater analgesic onset than with Ketamine ointment alone. This seems to be particularly true in the management of chronic low back pain. Ketamine ointment has not been found to be effective at all in reducing pain localized to the sacro-iliac joints of the low back. The Ketamine and BAB ointment, however, is able to substantially reduce pain for hours to days.
There also appears to be a comparative difference in the potency of the compounded ointments. This difference must be due to the synergy of the combination. In clinical testing, BAB or Ketamine alone could not generate the pain relief observed with the combination. Most importantly are the added indications of SIJ and Osteoarthritis pain. Ketamine alone was never able to have any positive impact on these two conditions. Also of note is that over time, with Reflex Sympathetic Dystrophy (RSD) in particular, the amount and frequency of dosing to get the same amount of pain relief decreases.
The theoretical advantage of combining Ketamine and BAB is explained by the following mechanism: Ketamine's analgesic properties are due to a link with opioid receptors even though interaction with other receptors (NMDA) and with other neurotransmission systems is also documented. At least part of the analgesic properties are due to interaction with adrenergic, cholinergic, and 5-HT receptors, and voltage-dependent calcium channels. This has a profound affect on local inflammatory response to injury by suppressing sympathetic initiation of the inflammatory reaction and pain. BAB acts on fast sodium channels so that C and A-delta nerve fiber activity is suppressed to prevent post-injury pain. The advantage is that sensory blockade is achieved without loss of motor activity and the protective sensory response to pain, as would occur with other anesthetics.
The advantages of the Ketamine and BAB ointment combination are more fully described under the Summary of the Invention and the Preferred Embodiment sections of this application.